Ascorbic acid addition compound of sulfathiazole



Fatented Aug. 1 2, 1952 ASOORBIC ACID ADDITION GOMEOUND OF SULFATHIAZOLE Simon L. Ruskin, New York, N. Y., assignor, by"

mesne assignments, to Physiological Chemicals Company, New Rochelle, N. Y., a corporation.

of New York:

No Drawing. Application March 29, 1944,

Serial No. 528,612

Y 1 Claim.

. 1 I The present invention relates to ascorbic or laevo-ascorbic (cevitamic) acidderivatives of organic amino compounds, both acid addition products and salts and mixed addition products and salts, and particularly of sulfanilic acid and of sulfanilamides, includin sulfanilamide itself and its N '-derivatives, and also those derivatives wherein one or both of the hydrogens of the nuclearly bound amino group are replaced by an acyl or other group, including derivatives wherein the sulfonarnide group is substituted by an alkylol group, the hydroxy group being free for reaction with the ascorbic acid to form an ester.

The present application is a continuation-inpart of my copending application Ser. No. 457,598, filed September 7, 1942, now Patent No. 2,419,230, Which in turn is a continuation-in-part of my application, Ser. No. 192,789, filed February 26, 1938, which issued as Patent No. 2,294,937, on September 8, 1942.

It is the general object of the invention to improve the physiological and/or physical properties of organic amino compounds having therapeutic activity and having a basic group, such as NHz or alcoholic hydroxyl, by combining th same with ascorbic acid to form either a true salt or an addition compound, to efiect a reduction in the toxicity, an improvement in the solubility, a diminishing of irritation on injection, etc.

The toxicity of sulfanilamide and its derivatives, including its N'-acyl derivatives, sulfapyridine, s'ulfathiazole, sulfathiodiazole, sulfadiazine, sulfamerazine, etc., is well known; in fact, many of the known derivatives have been produced in the attempt to reduce the toxicity of the parent sulfanilamide. It also has been found that where the treatment of, for example, open wounds required both a sulfanilamide drug and an anaesthetic, such as novocaine, the latter acts antagonistically toward the bactericide, thereby considerably reducing its effectiveness.

I have found that by combining various therapeutic agents containing an amino group with ascorbic acid, either to form a true salt (as by reaction with an alcohol group) or an addition compound, or both, products of improved properties are obtained. These improvements consist generally in a reduced toxicity, an increased solubility, the elimination or reduction of irritating action on the tissues, and in the case of anaesthetics, like novocaine, the suppression of the antagonism toward sulfanilamide drugs, My improved compounds are of particular valu because they have associated or chemically incorporated therein a substance, namely, ascorbic (c1. zoo-239.65)

2 9 acid, which is a normal component of the blood and of body tissues, so that the modification of the known therapeutic agents does not involve the introduction of still another radical foreign to the animal organism. The combination of the normally toxic sulianilamides with ascorbic acid either in the form of acid addition products, or of esters by reaction with an alcohol hydroxyl group introduced into the sulfanilamide compound, as by substitution of N with an alkylol' group, or in both ways, thus involves a modification of the therapeutic agent which makes it more easily tolerated by the animal body.

The detoxicating action of ascorbic acid on the sulfanilamides is probably the result of the formation of a larger molecule with pronounced serum protein-combining power. This combining power with the serum protein permits a greater rate and degree of absorption of the therapeutic agent. Pick and his co-workers have shown that the toxicity of a substance introduced into the blood stream is inversely proportional to its ability to form serum protein complexes, and substances that do, not form the serum protein complexes are toxic and are usually excreted in the unc-ombined form. This isone of the underlying difiicul'ties with sulfonamide compounds, and in the process of excretion, they cause considerable kidney damage.' The ascorbateradical both'increases the utilization of the sulfonamide com-'- pound and acts as a protective mechanism in its excretion. 1;

The following examples illustrate several methods of manufacturing the improved compounds in accordance with the invention:

Example 1. -Prep'aration of acetylsulfanilyl ascorbic acid 7 g. (-7 mol) ascorbic acid were dissolved un der cooling with ice in 25 cc. dry pyridine. The solution was then treated slowly understirring and cooling with 10 g. mol) of acetylamino benzene sulfochloride, care being taken to keep the reaction temperature at 50 C. The reaction mixture was then placed on ice over night. The following day it was treated with excess ether. A heavy oil precipitated which turned to an amorphous semi-solid on being further washed with ether. The last traces of pyridine were removed in a vacuum desiccator at room temperature. The product showed no tendency to crystallize. It was soluble in water and alcohol, and insoluble in chloroform, acetone, benzene and ethyl acetate. The product was taken up in 50 cc. absolute ether and treated under stirring with 2 equivalents of 3 sodium ethoxide in 100 cc. absolute alcohol. The second equivalent of sodium ethoxide was added because of the pyridine hydrochloride present. An orange colored precipitate was obtained which became filterable on standing in the ice chest over night. Yield of sodium salt: 11g.

Example 2.-Preparation of sulfam'lamz'de ascorbatc 17.2 g. mol) sulfanilamideand 17.6 g. (1%) ascorbic acid were well mixed and then 75 cc. dry

methyl alcohol were added On heating to the li /f g. ascorbic acid in 200 mg. salt:

105 mg. ascorbic acid found 101 mg. ascorbic acid theory Example 3..Prepamtion of suZfanil-ethanolamide monoascorbate 4'7 g. mol) acetyl sulfanil chloride were slowly added under stirring to'24.5 g. /5 mol) ethanolamine dissolved in 100 cc. water, care being taken to keep the reaction temperature around 40 C. At the end of the reaction a thick paste was obtained which was allowed to stand on ice a few hours, and then filtered. Yield 51 g. or 9.8%. The crude product was dissolved in a mixture of 25 cc. water and 50 cc. 5 N sulfuric acid, and the resulting solution was then heated on a water bath for three hours. The darkened acid solution was then neutralized to a pH of about 10 with 30% sodium hydroxide and allowed to stand on ice over night. At thi point a heavy oil was obtained which crystallized on standing in the ice chest over night. The following day the resulting sulfanil-ethanolamide was filtered off and washed with a little cold water. It was purified by recrystalliz ing twice from 10 cc. boiling water to which animal charcoal had been added. At the end of the second purification the product precipitated as crystals. Yield 17 gm about 40 of theory.

Analysis:

N:12.61 found 12.96% theory The reactions may be represented as follows:

EG 9 CE} 2.2 g. mol) sulfanil-ethanolamide and 1.8 g. ,5 mol) ascorbic acid were dissolved in cc.

4 dry methyl alcohol and boiled on a water bath until crystals began to show in the hot solution. The reaction mixture was then treated with 35 cc. chloroform and allowed to stand on ice over night. The following day pale yellow crystals of the mono-ascorbate were filtered off and washed with chloroform. Yield 3.8. g. or 95% theory.

To determine the amount of ascorbic acid present the salt was titrated with 0.1 N iodine solution.

Mg. ascorbic acid in 200 mg. salt:

92 .4 mg. found 89.0 mg. theory 4.-Preparation of suZfanil-ethanolamide di-asco'rbate 2.2 g. mol) sulfanil-ethanolamide and 3.6 g. mol) ascorbic acid were dissolved in 10 cc. dry methyl alcohol and boiled (with cover) on a water bath until crystals began to show in the hot solution. The reaction solution was then treated with 50 cc. chloroform and allowed to stand on ice over night. The following day dark yellow crystals of the di-ascorbate were filtered off and washed with chloroform. Yield 5.2 g. or theory.

To determine the amount of ascorbic acid present, the salt was titrated with 0.1 N iodine solution.

Mg. ascorbic acid in 200 mg. salt:

12? .6 mg. found 124.4 mg. theory The above product was also prepared in the following manner:

21.6 g. mol) sulfanilyl ethanolamide were dissolved in about 250 cc. absolute methyl alcohol. To this solution were added 35.2 g. A mol) of ascorbic acid and the solution concentrated until a greenish yellow color was obtained. It was then treated with three volumes of chloroform and allowed to stand on ice over night. The following day the precipitate was filtered off and washed with a little chloroform. Yield 56 g. or practically quantitative. Titration with iodine showed the formation of a double ascorbate.

Example Example 5.Pre;oaration of salfathiazole ascorbate 176 g. (1 mol) ascorbic acid and 223 g. (1 mol) sulfathiazole were dissolved in 3600 cc. methyl alcohol and the solution refluxed for approximately fifteen minutes. The yellow solution was filtered by suction and concentrated to 1500 cc. at atmospheric pressure on the Water bath. At this point a heavy precipitate began to form. The reaction mixture was then treated with 3000 cc. chloroform under stirring. A voluminous yellow precipitate was obtained. After standing in the ice chest over night it was filtered and washed with a little chloroform. It was then air dried to constant weight. Yield 365 grams or 91%.

Titration for ascorbic acid:

224 mg. ascorbic in 500 mg. salt found 220 mg. ascorbic in 500 mg. salt theory Example 6.-Preparation of sulfadiazz'ne ascorbate 5 g. (0.02 mol) sulfadiazine and 3.5 g. (0.02 mol) ascorbic acid were stirred in cc. pyridine, and the pyridine distilled off at reduced pressure until a clear yellow solution was ob tained. The distillation was then continued until crystallization began again. The reaction mixture at this point was approximately cc. It was then treated under stirring with 100 cc. chloroform.; After cooling in the ice chest a yellow precipitate was obtained. Yield 5.5 g. 01' 55%. Titration with iodine showed an excess of approximately 55% sulfadiazine. Y

The reaction may also be carried out by dis-1 solving equimolecular quantities of ,suliadiazlne and ascorbic acid in a minimum amount of propyleneglycol-and then precipitating the resulting double salt with five volumes of chloroform.

Example 7.Preparatz'on of sulfamerazz'ne ascorbate 5.3 g. (0.02 mol) sulfamerazine and 7.0 g. (0.04 mol) ascorbic acid were heated together in cc. propylene glycol until solution was complete. This takes place at approximately 125 C.,-a deep orange solutionbeing obtained. The reaction mixture was then, cooled toroom temperature and treated under stirring with 150 cc. chloroform. On cooling in the ice chest, crystallization took place. The yellow crystalswere filtered by suction, washed with asmall amount of chloroform and air dried. Yield 8.8 g. or theory for a mono ascorbate. Titration with iodine showed that one molecule of ascorbic acid had reacted with one molecule of sulfamerazine. Formula-- C11H1202N4SC6H806. I

The reaction may also be carried out by dissolving equimolecular quantities of sulfamerazine and ascorbic acid in a minimum amount of pyridine and precipitating with five volumes of chloroform.

ExampZe 8.Prepamtion of strychm'ne ascorbate Example 9.-Novocaz'ne ascorbate 23.6 g. mole) novocaine and 17.6 g. mol) ascorbic acid were warmed with about 200 cc. absolute methyl alcohol until solution was complete. The resulting solution was then slowly treated under stirring and cooling with 500 cc. chloroform or acetone. A yellow precipitate was obtained, which hardened on standing over night in the ice chest. Yield 40 g. or almost quantitative. The ascorbates of cocaine and atropine may be similarly prepared.

In certain of the above reactions, as in the reaction between sulfanilamide and ascorbic acid, a small proportion of zinc chloride may be employed as catalyst in the salt or ester formation.

That some sort of chemical combination takes place between the amino compounds above described and ascorbic acid is evident, for example, from the fact that in the case of sulfanilamidc ascorbate, greater solubility in methyl alcohol is obtained than is possessed either by sulfanilamide or by ascorbic acid. As this product is the salt of a relatively weak acid and relatively weak base, it hydrolyzes to a large extent in water; nevertheless, the ascorbate appears to be less toxic in wound serum then sulfanilamide alone. In the form of the ascorbate, or in the presence of a substantially equivalent amount of ascorbic acid, the solubility of sulfanilamide in water is increased from about 0.8% to about 1.2%.- This increase in solubility with simultaneous reduction in toxicity greatly enhances the therapeutic value of the sulfanilamide.

While in certain of the above examples I have describedthe use of N acetyl derivatives, such acetylated compound was presented only by way of example; for other acyl groups may be substituted in the para-amino group, such as propionyl, valeryl, benzoyLand the like. Where it is desired to form the ester of a sulfonalkylolamidecompound with ascorbic acid while keeping the para-aminogroup unsubstituted,- the corresponding para-nitro compound may be used as starting material and the para-nitro-benzenesulfonalkylolamide ascorbate then converted'to the corresponding para-amino compound by careful reduction, as by means of activated hydrogen in the manner well understood in the art.

In place of the ethanolamine, other alkylolamines. may be used, such as propanolamine, butanolamine, as well as their isomers and the higher alkylolamines.

I-Ieterocyclic compounds having a reactive amino group are also suitable for the production of valuable therapeutic compounds. For instance, one may employ the 2.6 diamino Z-ethyl pyridine, which possesses anaesthetic properties, and bring the same into reactive contact with ascorbic acid to cause the formation of an aminoethyl-pyridine-amino-ascorbate having considerably improved properties. Other compounds of analogous character and having the pyridine or quinoline nucleus may be employed in this reaction.

Many di-azo compounds are known which have found application as valuable anti-bacterial agents and have aryl as well as heterocyclic groups may be combined in accordance with the present invention. As typical of such compounds one may take the 3.6 diamino Z-methyl 5-phenylazo pyradine and combine the same with ascorbic acid as above explained. Other compounds of the azo type having two heterocyclic radicals are also applicable to the present invention; for example, the 2.6 diamino 3-pyridylazo pyridine may be coupled with the ascorbic acid to give bactericidal compounds of improved value. Also available are similar compounds having substituent groups in place of one or more of the free hydrogens on the rings, such as halogen, hydroxy, alkoxy, alkyl, aryl, and the like.

From the above it will be seen that a very large variety of therapeutic compounds of diverse characters are suitable for combination with ascorbic acid, forming compounds of enhanced value. While the character of the compounds may vary widely, it is essential that there be present an amino group capable of combining with an acid group under the conditions stated. above or under other conditions well known to the skilled chemist; or else, an alkylol group having a free hydroxyl capable of reacting with ascorbic acid.

The dosage of my improved compounds can be made the same as the corresponding known compounds; however, because of generally improved therapeutic ratio, somewhat lower dosages may be relied on. My improved products can be administered orally or parenterally, or applied to open wounds, just like the corresponding known compounds.

The ascorbic acid derivatives above described can be administered in the form of tablets, powders or solutions. The tablets can be of one-half and one gram size while aqueous solutions of one and one-half percent strength can be prepared and marketed in 10 cc. ampules. The powder can be packaged in paper shaker containers of five gram contents for the insufilation of wounds. Especially in the open wound treatment the ascorbate derivatives of the sulfanilamides are of particular advantage because they tend to clot globulin and thereby prevent or reduce hemorrhage. The ascorbate radical also tends to make the sulfanilamide compound more effective since the latter tends to cake in the presence of blood serum; the ascorbates, howevenbe'ing generally hygroscopic, form. a loose mass.

'In addition to the ascorbic acid compounds or ascorbic acid derivatives of organicamino compounds having physiological activity the corresponding derivatives of the ptomaines, putrescine. cadaverine-and 'tyramine have been found by me to have valuable therapeutic properties. These toxic amines are detoxified in the form of their ascorbic acid compounds; thus the injection of cadaverine ascorbate and of the other ptomaine ascorbates, in small doses tends to immunize the patient against these toxic amino compounds. Such treatment is particularly useful in the case of ulcero-necrotic lesions due to Vincents infections and in other conditions as sociated with cavitation. Valuable therapeutic agents are formed also by treating other alkaloids, like the cinchona alkaloids, including quinine and its derivatives, quinidine, cinchonine, etc. with ascorbic acid, to form the salts or esters. In each case improved solubility, reduced toxicity and/or better absorption or therapeutic REFERENCES CITED The following references are of record in the file ofthis patent:

-UNITED STATES PATENTS Number Name Date 2,132,662 Volwiler et a1. Oct. 11, 1938 2,1342% Elger Oct, 25, 1938 2,140,989 'Eisenbrandetal. Dec. 20, 1938 2,150,140 Warnat Mar. 7, 1939 2,283,817 Marti-net a1. May 19, 1942 2,294,937 Ruskin Sept. 8, 1942 2,419,230 Ruskin Apr. 22,1947

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